Exploring the Clinical Implication of S100A9 in Ulcerative Colitis and Its Progression to Cancer: A Journey from Inflammation to Cancer

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation and debilitating symptoms that considerably impair life quality. UC is particularly prevalent in younger populations, where early diagnosis remains challenging owing to nonspecific symptoms and the potential progression to colitis-associated cancer (CAC). The GSE177044 dataset, consisting of whole blood samples, was analyzed to identify differentially expressed genes, perform gene annotation, analyze key signaling pathways, and detect key hub genes in UC using protein-protein interaction networks. Multiple UC datasets composed of colonic samples were used for validation and examination of methylation and age-related gene expression patterns. Further analyses were performed to explore the association between these key hub genes and colon adenocarcinoma (COAD). We identified four key hub genes-lipocalin-2 (<i>LCN2</i>), matrix metalloproteinase-9 (<i>MMP9</i>), S100 calcium-binding protein A9 (<i>S100A9</i>), and olfactomedin-4 (<i>OLFM4</i>)-significantly up-regulated in UC, with <i>S100A9</i> showing epigenetic regulation and age-dependent expression patterns. Additionally, S100A9 was strongly associated with poor prognosis in COAD, displaying hypo-methylation and elevated expression, especially in myeloid cell types, and links to altered immune and molecular subtypes. Our findings confirmed the hypo-methylation-driven up-regulation of <i>LCN2</i>, <i>S100A9</i>, and <i>OLFM4</i> in UC, suggesting their potential as blood-based diagnostic biomarkers. Notably, S100A9 has emerged as a promising biomarker for the early diagnosis of ulcerative colitis, particularly in pediatric and adolescent patients with UC. Moreover, S100A9 holds potential as a precision target to prevent progression from UC to CAC.